MAP3K3

Protein-coding gene in the species Homo sapiens
MAP3K3
Available structures
PDBOrtholog search: PDBe RCSB
List of PDB id codes

2C60, 2JRH, 2PPH, 4Y5O, 4YL6, 2O2V

Identifiers
AliasesMAP3K3, MAPKKK3, MEKK3, mitogen-activated protein kinase kinase kinase 3
External IDsOMIM: 602539 MGI: 1346874 HomoloGene: 69110 GeneCards: MAP3K3
Gene location (Human)
Chromosome 17 (human)
Chr.Chromosome 17 (human)[1]
Chromosome 17 (human)
Genomic location for MAP3K3
Genomic location for MAP3K3
Band17q23.3Start63,622,415 bp[1]
End63,696,305 bp[1]
Gene location (Mouse)
Chromosome 11 (mouse)
Chr.Chromosome 11 (mouse)[2]
Chromosome 11 (mouse)
Genomic location for MAP3K3
Genomic location for MAP3K3
Band11|11 E1Start105,975,439 bp[2]
End106,046,272 bp[2]
RNA expression pattern
Bgee
HumanMouse (ortholog)
Top expressed in
  • monocyte

  • blood

  • gastric mucosa

  • right lung

  • right coronary artery

  • popliteal artery

  • spleen

  • upper lobe of left lung

  • left coronary artery

  • tibial nerve
Top expressed in
  • internal carotid artery

  • ascending aorta

  • aortic valve

  • external carotid artery

  • fossa

  • condyle

  • blood

  • Paneth cell

  • right lung lobe

  • lip
More reference expression data
BioGPS
More reference expression data
Gene ontology
Molecular function
  • ATP binding
  • protein kinase activity
  • protein binding
  • MAP kinase kinase kinase activity
  • kinase activity
  • metal ion binding
  • nucleotide binding
  • transferase activity
  • protein serine/threonine kinase activity
Cellular component
  • cytosol
  • cytoplasm
Biological process
  • intracellular signal transduction
  • protein phosphorylation
  • positive regulation of p38MAPK cascade
  • protein autophosphorylation
  • blood vessel development
  • phosphorylation
  • positive regulation of I-kappaB kinase/NF-kappaB signaling
  • regulation of mitotic cell cycle
  • stress-activated protein kinase signaling cascade
  • activation of protein kinase activity
  • regulation of apoptotic process
  • MAPK cascade
  • interleukin-1-mediated signaling pathway
  • positive regulation of cell proliferation in bone marrow
  • positive regulation of cell migration involved in sprouting angiogenesis
  • negative regulation of cellular senescence
  • signal transduction
Sources:Amigo / QuickGO
Orthologs
SpeciesHumanMouse
Entrez

4215

26406

Ensembl

ENSG00000198909

ENSMUSG00000020700

UniProt

Q99759

Q61084

RefSeq (mRNA)

NM_002401
NM_203351
NM_001330431
NM_001363768

NM_011947

RefSeq (protein)

NP_001317360
NP_002392
NP_976226
NP_001350697

NP_036077

Location (UCSC)Chr 17: 63.62 – 63.7 MbChr 11: 105.98 – 106.05 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Mitogen-activated protein kinase kinase kinase 3 is an enzyme that in humans is encoded by the MAP3K3 gene,[5] which is located on the long arm of chromosome 17 (17q23.3).[6]

Function

This gene product is a 626-amino acid polypeptide that is 96.5% identical to mouse MEKK3. Its catalytic domain is closely related to those of several other kinases, including mouse MEKK2, tobacco NPK, and yeast STE11. Northern blot analysis revealed a 4.6-kb transcript that appears to be ubiquitously expressed.

MAP3Ks are involved in regulating cell fate in response to external stimuli.[7] MAP3K3 directly regulates the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 respectively. In cotransfection assays, it enhanced transcription from a nuclear factor kappa-B (NF-κB)-dependent reporter gene, consistent with a role in the SAPK pathway. Alternatively spliced transcript variants encoding distinct isoforms have been observed.[8] MEKK3 regulates the p38, JNK and ERK1/2 pathways.[7]

Interactions

MAP3K3 has been shown to interact with [SQSTM1/p62],:

MAP3K3 in cancer

Two SNPs in the MAP3K3 gene were found as candidates for association with colon and rectal cancers.[15]

MEKK3 is highly expressed in 4 ovarian cancer cell lines (OVCA429, Hey, DOV13, and SKOv3). This expression level is significantly higher in those cancer cells when compared to normal cells. MEKK3 expression levels are comparable to IKK kinase activities, which also relate to activation of NFκB. High expression of MEKK3 in most of these ovarian cancer cells supposedly activate IKK kinase activity, which lead to increased levels of active NFκB. Also, MEKK3 interacts with AKT to activate NFκB. Genes related to cell survival and anti-apoptosis have increased expression in most cancer cells with high levels of MEKK3. This is probably due to constitutive activation of NFκB, which will regulate those genes. In this sense, knockdown of MEKK3 caused ovarian cancer cells to be more sensitive to drugs.[10]

MEKK3 also interacts with BRCA1. Knocking down BRCA1 resulted in inhibited MEKK3 kinase activity. The drug paclitaxel induces MEKK3 activity and it requires functional BRCA1 to do it. It was observed that in a breast cancer cell line BRCA1-deficient (HCC1937), paclitaxel was unable to activate MEKK3. Paclitaxel may be inducing stress-response through the MEKK3/JNK/p38/MAPK pathway, but not in mutated BRCA1 cells.[9]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000198909 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020700 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Ellinger-Ziegelbauer H, Brown K, Kelly K, Siebenlist U (Jan 1997). "Direct activation of the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by an inducible mitogen-activated protein Kinase/ERK kinase kinase 3 (MEKK) derivative". The Journal of Biological Chemistry. 272 (5): 2668–74. doi:10.1074/jbc.272.5.2668. PMID 9006902.
  6. ^ MAP3K3 in GeneCards – The Human Gene Compendium. https://www.genecards.org/cgi-bin/carddisp.pl?gene=MAP3K3
  7. ^ a b Craig EA, Stevens MV, Vaillancourt RR, et al. (2008). "MAP3Ks as central regulators of cell fate during development". Developmental Dynamics. 237 (11): 3102–14. doi:10.1002/dvdy.21750. PMID 18855897. S2CID 876964.
  8. ^ "Entrez Gene: MAP3K3 mitogen-activated protein kinase kinase kinase 3".
  9. ^ a b Gilmore PM, McCabe N, Quinn JE, Kennedy RD, Gorski JJ, Andrews HN, McWilliams S, Carty M, Mullan PB, Duprex WP, Liu ET, Johnston PG, Harkin DP (Jun 2004). "BRCA1 interacts with and is required for paclitaxel-induced activation of mitogen-activated protein kinase kinase kinase 3". Cancer Research. 64 (12): 4148–54. doi:10.1158/0008-5472.CAN-03-4080. PMID 15205325.
  10. ^ a b Samanta AK, Huang HJ, Le XF, Mao W, Lu KH, Bast RC, Liao WS (Sep 2009). "MEKK3 expression correlates with nuclear factor kappa B activity and with expression of antiapoptotic genes in serous ovarian carcinoma". Cancer. 115 (17): 3897–908. doi:10.1002/cncr.24445. PMC 3061353. PMID 19517469.
  11. ^ Che W, Lerner-Marmarosh N, Huang Q, Osawa M, Ohta S, Yoshizumi M, Glassman M, Lee JD, Yan C, Berk BC, Abe J (Jun 2002). "Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-alpha-induced c-Jun and NF-kappaB activation and adhesion molecule expression". Circulation Research. 90 (11): 1222–30. doi:10.1161/01.RES.0000021127.83364.7D. PMID 12065326.
  12. ^ Sun W, Kesavan K, Schaefer BC, Garrington TP, Ware M, Johnson NL, Gelfand EW, Johnson GL (Feb 2001). "MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway". The Journal of Biological Chemistry. 276 (7): 5093–100. doi:10.1074/jbc.M003719200. PMID 11073940.
  13. ^ Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G (Feb 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology. 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216. S2CID 11683986.
  14. ^ Fanger GR, Widmann C, Porter AC, Sather S, Johnson GL, Vaillancourt RR (Feb 1998). "14-3-3 proteins interact with specific MEK kinases". The Journal of Biological Chemistry. 273 (6): 3476–83. doi:10.1074/jbc.273.6.3476. PMID 9452471.
  15. ^ Slattery ML, Lundgreen A, Wolff RK (2012). "MAP kinase genes and colon and rectal cancer". Carcinogenesis. 33 (12): 2398–408. doi:10.1093/carcin/bgs305. PMC 3510742. PMID 23027623.

Further reading

  • Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
  • Bonaldo MF, Lennon G, Soares MB (Sep 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
  • Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
  • Fanger GR, Widmann C, Porter AC, Sather S, Johnson GL, Vaillancourt RR (Feb 1998). "14-3-3 proteins interact with specific MEK kinases". The Journal of Biological Chemistry. 273 (6): 3476–83. doi:10.1074/jbc.273.6.3476. PMID 9452471.
  • Chao TH, Hayashi M, Tapping RI, Kato Y, Lee JD (Dec 1999). "MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathway". The Journal of Biological Chemistry. 274 (51): 36035–8. doi:10.1074/jbc.274.51.36035. PMID 10593883.
  • Yang J, Boerm M, McCarty M, Bucana C, Fidler IJ, Zhuang Y, Su B (Mar 2000). "Mekk3 is essential for early embryonic cardiovascular development". Nature Genetics. 24 (3): 309–13. doi:10.1038/73550. PMID 10700190. S2CID 23203939.
  • Sun W, Kesavan K, Schaefer BC, Garrington TP, Ware M, Johnson NL, Gelfand EW, Johnson GL (Feb 2001). "MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway". The Journal of Biological Chemistry. 276 (7): 5093–100. doi:10.1074/jbc.M003719200. PMID 11073940.
  • Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
  • Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A (Mar 2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Research. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
  • Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S (Sep 2000). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Reports. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC 1083732. PMID 11256614.
  • Yang J, Lin Y, Guo Z, Cheng J, Huang J, Deng L, Liao W, Chen Z, Liu Z, Su B (Jul 2001). "The essential role of MEKK3 in TNF-induced NF-kappaB activation". Nature Immunology. 2 (7): 620–4. doi:10.1038/89769. PMID 11429546. S2CID 22382563.
  • Che W, Lerner-Marmarosh N, Huang Q, Osawa M, Ohta S, Yoshizumi M, Glassman M, Lee JD, Yan C, Berk BC, Abe J (Jun 2002). "Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-alpha-induced c-Jun and NF-kappaB activation and adhesion molecule expression". Circulation Research. 90 (11): 1222–30. doi:10.1161/01.RES.0000021127.83364.7D. PMID 12065326.
  • Lee CM, Onésime D, Reddy CD, Dhanasekaran N, Reddy EP (Oct 2002). "JLP: A scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors". Proceedings of the National Academy of Sciences of the United States of America. 99 (22): 14189–94. Bibcode:2002PNAS...9914189L. doi:10.1073/pnas.232310199. PMC 137859. PMID 12391307.
  • Adams DG, Sachs NA, Vaillancourt RR (Nov 2002). "Phosphorylation of the stress-activated protein kinase, MEKK3, at serine 166". Archives of Biochemistry and Biophysics. 407 (1): 103–16. doi:10.1016/S0003-9861(02)00464-2. PMID 12392720.
  • Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y, Doi T, Shimotohno K, Harada T, Nishida E, Hayashi H, Sugano S (May 2003). "Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways". Oncogene. 22 (21): 3307–18. doi:10.1038/sj.onc.1206406. PMID 12761501.
  • Nakamura K, Johnson GL (Sep 2003). "PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway". The Journal of Biological Chemistry. 278 (39): 36989–92. doi:10.1074/jbc.C300313200. PMID 12912994.
  • Huang Q, Yang J, Lin Y, Walker C, Cheng J, Liu ZG, Su B (Jan 2004). "Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3". Nature Immunology. 5 (1): 98–103. doi:10.1038/ni1014. PMID 14661019. S2CID 24806598.
  • Samanta AK, Huang HJ, Bast RC, Liao WS (Feb 2004). "Overexpression of MEKK3 confers resistance to apoptosis through activation of NFkappaB". The Journal of Biological Chemistry. 279 (9): 7576–83. doi:10.1074/jbc.M311659200. PMID 14662759.
  • Stevens MV, Broka DM, Parker P, Rogowitz E, Vaillancourt RR, Camenisch TD (Dec 2008). "MEKK3 initiates transforming growth factor beta 2-dependent epithelial-to-mesenchymal transition during endocardial cushion morphogenesis". Circulation Research. 103 (12): 1430–40. doi:10.1161/CIRCRESAHA.108.180752. PMC 2728220. PMID 19008476.
  • v
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  • 2c60: CRYSTAL STRUCTURE OF HUMAN MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 3 ISOFORM 2 PHOX DOMAIN AT 1.25 A RESOLUTION
    2c60: CRYSTAL STRUCTURE OF HUMAN MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE 3 ISOFORM 2 PHOX DOMAIN AT 1.25 A RESOLUTION
  • 2o2v: Crystal Structure of the Complex of Human Mitogen Activated Protein Kinase Kinase 5 Phox Domain (MAP2K5-phox) with Human Mitogen Activated Protein Kinase Kinase Kinase 3 (MAP3K3B-phox)
    2o2v: Crystal Structure of the Complex of Human Mitogen Activated Protein Kinase Kinase 5 Phox Domain (MAP2K5-phox) with Human Mitogen Activated Protein Kinase Kinase Kinase 3 (MAP3K3B-phox)
  • 2pph: solution structure of human MEKK3 PB1 domain
    2pph: solution structure of human MEKK3 PB1 domain
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Non-specific serine/threonine protein kinases (EC 2.7.11.1)
Pyruvate dehydrogenase kinase (EC 2.7.11.2)
Dephospho-(reductase kinase) kinase (EC 2.7.11.3)
3-methyl-2-oxobutanoate dehydrogenase (acetyl-transferring) kinase (EC 2.7.11.4)
(isocitrate dehydrogenase (NADP+)) kinase (EC 2.7.11.5)
(tyrosine 3-monooxygenase) kinase (EC 2.7.11.6)
Myosin-heavy-chain kinase (EC 2.7.11.7)
Fas-activated serine/threonine kinase (EC 2.7.11.8)
Goodpasture-antigen-binding protein kinase (EC 2.7.11.9)
  • -
IκB kinase (EC 2.7.11.10)
cAMP-dependent protein kinase (EC 2.7.11.11)
cGMP-dependent protein kinase (EC 2.7.11.12)
Protein kinase C (EC 2.7.11.13)
Rhodopsin kinase (EC 2.7.11.14)
Beta adrenergic receptor kinase (EC 2.7.11.15)
G-protein coupled receptor kinases (EC 2.7.11.16)
Ca2+/calmodulin-dependent (EC 2.7.11.17)
Myosin light-chain kinase (EC 2.7.11.18)
Phosphorylase kinase (EC 2.7.11.19)
Elongation factor 2 kinase (EC 2.7.11.20)
Polo kinase (EC 2.7.11.21)
Serine/threonine-specific protein kinases (EC 2.7.11.21-EC 2.7.11.30)
Polo kinase (EC 2.7.11.21)
Cyclin-dependent kinase (EC 2.7.11.22)
(RNA-polymerase)-subunit kinase (EC 2.7.11.23)
Mitogen-activated protein kinase (EC 2.7.11.24)
MAP3K (EC 2.7.11.25)
Tau-protein kinase (EC 2.7.11.26)
(acetyl-CoA carboxylase) kinase (EC 2.7.11.27)
  • -
Tropomyosin kinase (EC 2.7.11.28)
  • -
Low-density-lipoprotein receptor kinase (EC 2.7.11.29)
  • -
Receptor protein serine/threonine kinase (EC 2.7.11.30)
MAP2K
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